Glutamic acid is the major excitatory amino acid in the mammalian central nervous system (CNS), and acts through two classes of receptors, the ionotropic and metabotrobic receptors, respectively. The ionotropic glutamate receptors are divided into three subtypes based on the affinities of agonists for these receptors, namely N-methyl-D-aspartate (NMDA), (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) and kainic acid (or kainate) receptors.
The NMDA receptor contains binding sites for modulatory compounds such as glycine and polyamines. Binding of glycine to its receptor enhances the NMDA receptor activation. Such NMDA receptor activation may, be a potential target for the treatment of schizophrenia and other diseases linked to NMDA receptor dysfunction. An activation can be achieved by an inhibitor of the glycine transporter.
Molecular cloning has revealed the existence of two types of glycine transporters, GlyT-1 and GlyT-2, wherein GlyT-1 can be further subdivided into GlyT-1a, GlyT-1b and GlyT-1c.
The NMDA receptor is blocked by compounds such as phencyclidine which induce a psychotic state which resembles schizophrenia. Likewise, the NMDA antagonists, such as ketamine, induce negative and cognitive symptoms similar to schizophrenia. This indicates that NMDA receptor dysfunction is involved in the pathophysiology of schizophrenia.
The NMDA receptor has been associated with a number of diseases, such as pain (Yaksh Pain 1989, 37, 111–123), spasticity, myuoclonus and epilepsy (Truong et. al. Movement Disorders 1988, 3, 77–87), learning and memory (Rison et. al. Neurosci. Biobehav. Rev. 1995, 19, 533–552).
Glycine transporter antagonists or inhibitors are believed to be highly beneficial in the treatment of schizophrenia (Javitt WO 97/20533).
Glycine transport antagonists or inhibitors could be useful for the treatment of both the positive and the negative symptoms of schizophrenia and other psychoses, and in the improvement of cognition in conditions where the cognitive processes are diminished, i.e. Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or diseases wherein the brain is damaged by inner or outer influence, such as trauma to the head or stroke. Likewise, convulsive disorders such as epilepsy, spasticity or myoclonus may benefit from glycine transporter antagonists.
Clinical trials with glycine have been reported, Javitt et. al. Am. J. Psychiatry 1994, 151, 1234–1236 and Leiderman et. al. Biol. Psychiatry 1996, 39, 213–215. The treatment with high-dose glycine is reported to improve the symptoms of schizophrenia. There is a need for more efficient compounds for the treatment of NMDA associated diseases.
The present invention provides compounds which are potent inhibitors of the glycine transporter and consequently they are useful in treating diseases associated with NMDA dysfunction.